The overall goal of this proposal is to test a novel concept in breast cancer prevention. Reducing breast cancer incidence can theoretically have a profound impact on saving lives and reducing the huge cost of treatment. Antiestrogens can prevent breast cancer, but they require prolonged treatment and can have significant side effects. Therefore, new preventive therapy that does not require years of continuous treatment is urgently needed. Premalignant lesions of the breast sometimes but not always progress to invasive cancer - what causes this small subset of premalignant lesions to progress is not yet known. Studies in several tissue types indicate that apoptosis is activated in human premalignant lesions as a result of oncogene overexpression and oncogene-induced aberrant proliferation, providing a barrier to progression to malignancy. This barrier must be overcome for early lesions to develop into full-blown cancer. In our preliminary studies using mouse models, we have found that Jak2-STAT5 signaling may be a key pathway that can break this anticancer barrier. Therefore, we hypothesize that the JAK2-STAT5 pathway in human premalignant lesions promotes the progression to malignancy by lowering the apoptosis anticancer barrier; if so, inhibition of this prosurvival pathway could reduce the load of premalignant lesions in the breast and thus lower breast cancer risk. We predict that even transient or intermittent inhibition of this pathway in early lesions could devitalize them and lower the risk of invasive breast cancer, while the possible adverse effects, cost, and inconvenience to women would be small. Three aims are as follows: Aim 1: Determine if STAT5 activation accelerates tumorigenesis of premalignant lesions induced by major oncogenic events associated with breast cancer. Aim 2: Determine whether in rodent models short-term or intermittent administration of ruxolitinib causes apoptosis in pSTAT5-expressing early lesions and effectively prevents their progression to cancer. Aim 3: Determine whether in women with a premalignant lesion on core biopsy requiring subsequent surgical resection, short-term ruxolifinib blocks pSTAT5 and induces apoptosis in the lesion.